Biology subjects

Volpato, V.

Publications and source records attributed to Volpato, V..

4 recordsLinked to original sources

bioRxiv2025

A highly efficient method to differentiate CGRP-expressing peptidergic nociceptors from human induced pluripotent stem cells

Human cellular models of disease developed using induced pluripotent stem cells (iPSC) have enabled wide-ranging research from investigation of human disease mechanisms to phenotypic drug screens. Pain disorders such as neuropathic pain and headache remain areas of considerable unmet need and are considered high risk by pharma. Human iPSC-derived sensory neurons have already been used to accelerate translational research but the current differentiation protocols produce non-peptidergic nociceptors. We demonstrate for the first time the robust differentiation of hiPSC into peptidergic nociceptor lineage with high yield. These nociceptors express CGRP and TRPV1 whilst the non-peptidergic marker RET was completely absent. Functionally, the nociceptors show functional maturity including the expression of TTX-resistant currents and responding to TRPV1 and TRPA1 agonists. Importantly, they were able to release CGRP basally and upon stimulation by an inflammatory soup, which was inhibited upon the application of the 5-HT1B/1D/1F agonist, sumatriptan and topiramate, a migraine prophylactic drug. Overall, we report the successful generation of a novel in vitro functional peptidergic nociceptor model which will allow investigation of disease mechanisms in pain and for the development of new effective pain therapies.

neuroscience↗

bioRxiv2024

Differential growth and transcriptomic profile in stem cell-derived midbrain astrocytes

The regional specificity of stem cell-derived astrocytes is believed to be an important prerequisite for their application in disease modelling and cell-based therapies. Due to the lack of subtype-defining markers for astrocytes in different regions of the brain, the regional identity of in vitro-derived astrocytes is often declared by the dominant positional characteristics of their antecedent neural progenitors, patterned to a fate of interest, with the assumption that the positional trait is preserved by the derived astrocytes via linear descent. Using a human induced pluripotent stem cell line designed for tracing derivatives of LMX1A+ cells combined with a ventral midbrain induction paradigm, we show that astrocytes originating from LMX1A+ progenitors can only be generated if these progenitors are purified prior to the astrocyte differentiation process, or their progenies are gradually lost to progenies of LMX1A- progenitors. This finding indicates that the lineage composition of iPSC-derived astrocytes may not accurately recapitulate the founder progenitor population. Using deep single-cell RNA sequencing, we identified distinct transcriptomic signatures in astrocytes derived from the LMX1A+ progenitor cells. Our study highlights the need for rigorous characterization of pluripotent stem cell-derived regional astrocytes, and provides a resource for assessing LMX1A+ ventral midbrain progenitor-derived human astrocytes.

developmental biology↗

bioRxiv2020

A human single-cell atlas of the Substantia nigra reveals novel cell-specific pathways associated with the genetic risk of Parkinson's disease and neuropsychiatric disorders.

We describe a human single-nuclei transcriptomic atlas for the Substantia nigra (SN), generated by sequencing ~ 17,000 nuclei from matched cortical and SN samples. We show that the common genetic risk for Parkinsons disease (PD) is associated with dopaminergic neuron (DaN)-specific gene expression, including mitochondrial functioning, protein folding and ubiquitination pathways. We identify a distinct cell type association between PD risk and oligodendrocyte-specific gene expression. Unlike Alzheimers disease (AD), we find no association between PD risk and microglia or astrocytes, suggesting that neuroinflammation plays a less causal role in PD than AD. Beyond PD, we find associations between SN DaNs and GABAergic neuron gene expression patterns with multiple neuropsychiatric disorders. Nevertheless, we find that each neuropsychiatric disorder is associated with a distinct set of genes within that neuron type. This atlas guides our aetiological understanding by associating SN cell type expression profiles with specific disease risk.

neuroscience↗

bioRxiv2019

Combining multi-omics and drug perturbation profiles to identify novel treatments that improve disease phenotypes in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss of survival motor neuron (SMN) protein. While SMN restoration therapies are beneficial, they are not a cure. We aimed to identify novel treatments to alleviate muscle pathology combining transcriptomics, proteomics and perturbational datasets. This revealed potential drug candidates for repurposing in SMA. One of the lead candidates, harmine, was further investigated in cell and animal models, improving multiple disease phenotypes, including SMN expression and lifespan. Our work highlights the potential of multiple, parallel data driven approaches for development of novel treatments for use in combination with SMN restoration therapies.

neuroscience↗